Ongoing research provides further understanding of the biology of RNase A ribonucleases that promote innate immunity with efforts focused toward understanding their mechanisms of action in health and disease. Eosinophil derived neurotoxin (EDN) and eosinophil cationic protein (ECP) are prominent, evolutionarily divergent secretory mediators of human eosinophils with antiviral activity. The mouse orthologs of EDN and ECP, these proteins, the eosinophil-associated ribonucleases (EARs) have undergone an unusual pattern of evolution called rapid birth-death and gene-sorting, which has also been documented in the T-cell receptor, immunoglobulin, and major-histocompatability complex gene families (Zhang et al., 2000. Proc Natl Acad Sci U S A. 97:4701 - 4706). As part of our first publication in this report, we found that eosinophils recruited to the airways of otherwise nave mice in response to Aspergillus fumigatus sensitization and challenge are activated by and degranulate specifically in response to infection with the mouse pneumovirus pathogen, pneumonia virus of mice (PVM). Among the degranulation products, we specifically evaluated the release of mouse eosinophil associated ribonucleases (mEars), measured both enzymatically and via specific immunoreactivity. In this manuscript, we demonstrated that eosinophil activation and degranulation was associated with antiviral activity and survival in response to lethal virus infection. In our current work, we are examining the roles of specific granule proteins, including the eosinophil-specific mEars (Percopo et al., 2014. Blood 123:743-752) One specific mouse Ear, mEAR11 has retained the RNase A family characteristic sequence motifs but has a unique expression pattern, as it responds to Th2 stimulation, and is produced by alternatively-activated macrophages in the lung in response to IL-4 or IL-13 (Cormier et al., 2002. Am J Respir Cell Mol Biol. 2002 27:678-687). As part of a larger effort to evaluate the unique properties of mEAR11, we have compared the enzymatic activity of this protein to the predominant paralogs, mEAR1 and mEAR2. Despite similar isoelectric points (pI), mEAR11 has approximately 100-fold less activity against a standard tRNA substrate. In addition to its aforementioned responses to Th2 cytokines, we have shown that mEar 11 is expressed prominently in hematopoietic tissues and serves as a chemoattractant for F4/80+ macrophages. We also report a mouse model that includes the first successful deletion of a mouse eosinophil ribonuclease. The characterization of this mouse will have profound impact on our understanding of the role of these enzymes in promoting homeostasis in vivo and at the cellular level. (Yamada et al., 2014 manuscript in preparation).